Abstract There are currently no disease modifying therapies for AD but many disease-relevant pathways remain under- explored. This proposal seeks to understand the molecular mechanisms relating tau and TDP-43 pathology in the context of late-onset Alzheimer?s disease (AD) by combining human neuropathology and gene expression data with biological validation in a C. elegans model of proteotoxicity. Under the mentorship of Drs. Brain Kraemer and Dirk Keene, this training and research plan will build on Dr. Latimer?s expertise in neuropathology and prepare her for a career studying the proteotoxic pathways relevant to AD using C. elegans as a model system. C. elegans represent an ideal system for investigating mechanisms of human disease given their ease of transgenic modification, short life cycle, and recapitulation of the progressive neurodegeneration that is characteristic of human proteinopathies. The five-year training plan includes research mentored by an established team of experts and instruction in C. elegans research techniques, classification of TDP-43 proteinopathy, implementation of quantitative algorithms for immunohistochemistry in human tissue, and analysis and interpretation of RNA-Seq data. This training will provide Dr. Latimer with the interdisciplinary skills and knowledge necessary to achieve her long-term career goal to succeed as an independent physician scientist with the expertise to advance the field of AD pathophysiology using C. elegans models of proteotoxicity to link human pathology with the underlying mechanisms. Data from human cohorts suggest a role for TDP-43 in the clinical expression of AD neuropathologic change. This proposal will address the hypotheses that tau and TDP-43 synergize to drive neurodegeneration and that targeting both toxic proteins may have stronger protective effects than targeting either alone. The project builds on Dr. Latimer?s previous work with Drs. Kraemer and Liachko demonstrating the synergism between tau and TDP-43 in a C. elegans model of combined proteotoxicity, and autopsy data in the Adult Changes in Thought (ACT) study, a unique, longitudinal community-based cohort of older adults recruited from the Seattle area, in which TDP-43 pathology is associated with dementia and increased pathologic tau. Dr. Latimer will test known genetic modifiers of tau or TDP-43 neurotoxicity in the tau/TDP-43 C. elegans model (Aim 1) and determine whether TDP-43 and tau pathology correlate in human brain tissue, leveraging data from the ACT autopsy cohort (Aim 2). She will then use neuropathology data to select cases for RNA-Seq analysis in the ACT cohort to identify novel modifiers of tau and TDP-43 proteotoxicity that can be biologically validated in the tau/TDP-43 C. elegans model (Aim 3). Completion of the aims will set the stage for future independent funding using human genetic and neuropathologic data coupled with C. elegans models and lay the foundation for a new generation of AD therapeutics that can be further evaluated in other cohorts and model systems.